Therapeutic compositions and methods of use

ABSTRACT

According to the present invention, there is provided an admixture of sorbic acid, malic acid, fumaric acid, crotonic acid, and optionally aconitic acid. Further contemplated by the present invention are methods for treating various pathological conditions such as viral infections, acidosis, tumors, and bacterial and fungal infections by administering various therapeutically effective amounts of an admixture described above.

This application is a 370 of PCT/US94/06653 filed Aug. 6, 1994, whichclaim priority from U.S. patent application Ser. No. 08/073,934 filedJun. 8, 1993, now abandoned.

FIELD OF THE INVENTION

The invention relates to admixture compositions of short chain organicfatty acids which have biological effects. For example, they are usefulin the treatment of numerous pathologies that affect mammals. Theinvention also relates to methods of treatment of such pathologies,wherein appropriate therapeutically effective amounts of thecompositions are administered.

BACKGROUND OF THE INVENTION

A wide variety of carboxylic acid containing compositions arebiologically active, and several short chain organic acids which arenaturally occurring acids have previously been implicated in thetreatment of various pathological conditions. For example, Nordman, U.S.Pat. No. 3,291,689, discloses the treatment of hepatic ammoniaintoxication with a mixture of L-arginine and malic acid. U.S. Pat. No.3,718,664 discloses the use of thioctic acid derivatives in thetreatment of acidosis.

Sloan, U.S. Pat. No. 4,381,307, discloses soft tertiary amine esterderivatives that have biological effects, while U.S. Pat. No. 4,760,078discloses a 1,2, dithiol-3-thione derivative that has animmunomodulating effect.

Rubenstein, U.S. Pat. No. 4,971,760, discloses the sterilization ofblood, blood constituents, and transplant tissues with a disinfectantthat includes lactic acid and sodium chlorite. Naphtholic acidderivatives were discovered to be useful in enhancing oxygenavailability to mammalian tissue by Suh et al., U.S. Pat. No. 5,015,663.

Hoffiler et al., U.S. Pat. No. 5,043,357, disclose a virucidal agentthat is predominantly comprised of ethanol and/or alcohol but whichincludes a minor amount of a short chain organic acid. Further, U.S.Pat. No. 5,093,140 discloses an aqueous bactericide that containsorganic acids. This solution is used in the scalding or washing stagesof meat dressing. Kross et al., U.S. Pat. No. 5,100,652 disclose an oraldisinfectant that contains organic acids. See also Comroe et al., TheLung, 1955 Yearbook of Medical Publications Inc., Chptr. 4; John West,Respiratory Physiology, The Williams & Wilkins Co., Chptr. 6; Hypoxia,Metabolic Acidosis and Circulation, ARTCF . . . Oxford; Arnold et al,"Excessive Intracellular Acidosis of Skeletal Muscle on Exercise in aPatient with a Post-Viral Exhaustion/Fatigue Syndrome" The Lancet: Jun.23, 1984; Schweckendiek, W., "Heilung von Psoraiasis vulgaris", Med.SschS, 13:103-4, 1959; G. E. Abraham et al., "Rationale for the Use ofMagnesium and Malic Acid", Journal of Nutritional Medicine, 3:49-49(1992); Kuroda, Z. and Akano, M., "Antitumor and Anti-intoxicationActivities of Fumaric Acid in Cultured Cells", Gann, 727:77-782 (1981);Chemical Abstracts 98945Y, 116, March 1992 "Antifungal Activity ofFumarates in Mice Infected with C. Albicans"; Bauer et al., "ClinisheWochenschrift 1991 69(2), pp. 722-4; for further details of severalpathological processes which are susceptible to treatment according tothe present invention.

It has now been discovered that admixtures of specific short chainorganic acids have broad therapeutic effects.

SUMMARY OF THE INVENTION

According to the present invention, there is provided a compositionwhich comprises an admixture of sorbic acid, aconitic acid, malic acid,fumaric acid, crotonic acid, and optionally aconitic acid.

Further contemplated by the present invention are methods for treatingvarious pathological conditions such as viral infections including, butnot limited to, cytomegalovirus and hepatitis infections; acidosis;tumors; and bacterial and fungal infections, by administering varioustherapeutically effective amounts of the admixture described above.

DETAILED DESCRIPTION OF THE INVENTION

Organic acids are a large group of compounds, many of which can bederived from proteins, carbohydrates, and fats. Although many occurnaturally, many can be synthetically produced without great difficulty.

Sorbic acid is a crystalline diolefinic acid having the formula C₆ H₈O₂. Typically, it is used as mold and yeast inhibitor; a fungistaticagent for foods, especially cheeses; or to improve the characteristicsof drying oils, the gloss of alkyd type coatings, or the millingproperties of cold rubber.

Aconitic acid is a white crystalline acid having the formula C₆ H₆ O₆.Typically, it is used in manufacturing itaconic acid or as a plasticizerfor buna rubber and plastics.

Malic acid is a crystalline dicarboxylic acid having the formula C₄ H₄O₅ and is typically found in three isomeric crystalline forms.

Fumaric acid is a crystalline unsaturated dicarboxylic acid having theformula C₄ H₄ O₄. Fumaric acid is typically used as a substitute fortartaric acid in beverages and baking powders, as a replacement orpartial replacement of citric acid in soft drinks, and as anantioxidant.

Crotonic acid is an unsaturated aliphatic acid having the formula C₄ H₆O₂. It exists in the crystalline form, and is typically used in themanufacture of copolymers with vinylacetate that are used in lacquersand paper sizing, and in the manufacture of softening agents forsynthetic rubber.

It has now been discovered that these acids, in combination, havesignificant therapeutic value. The admixtures of these acids areprepared by conventional means known to those skilled in the skilledart. The order of addition of the acids to the admixture does not affectthe final composition.

Although a wide range of proportions of the individual components of theadmixture is effective, in a typical composition, each of the fourrequired individual acids will independently comprise from about 1 toabout 50 parts by weight and, optionally, aconitic acid will comprisefrom 0 to about 50 parts by weight, based upon 100 parts by weight ofthe five acids combined. Preferably, sorbic acid comprises from about 5to about 40 parts by weight, aconitic acid comprises from 0 to about 50parts by weight, malic acid comprises from about 1 to about 30 parts byweight, fumaric acid comprises from about 1 to about 30 parts by weight,and crotonic acid comprises from about 1 to about 30 parts by weight,based upon 100 parts by weight of the five acids combined. Mostpreferably, sorbic acid comprises from about 20 to about 30 parts byweight, aconitic acid comprises from about 35 to about 45 parts byweight, malic acid comprises from about 10 to about 20 parts by weight,fumaric acid comprises from about 10 to about 20 parts by weight, andcrotonic acid comprises from about 1 to about 20 parts by weight, basedupon 100 parts by weight of the five acids combined. Special mention ismade of an admixture wherein sorbic acid comprises about 24 parts byweight, aconitic acid comprises about 40 parts by weight, malic acidcomprises about 16 parts by weight, fumaric acid comprises about 16parts by weight, and crotonic acid comprises about 4 parts by weight,based upon 100 parts by weight of the five acids combined.

Suitable pharmaceutically active carriers may be combined with theadmixture. Such carriers include those known to those skilled in the artand can be added at any point in the mixing process. If apharmaceutically active carrier is used, the carrier will comprise fromabout 1 to about 99 parts by weight and the acid admixture will comprisefrom about 99 to about 1 part by weight, based upon 100 parts by weightof acid admixture and carrier combined.

The acid admixture with or without the carrier can be formulated intodosage unit forms including, but not limited to, capsules and tablets.Methods of preparation of dosage unit forms would be known to thoseskilled in the art. Agents which facilitate the manufacture and/or useof such dosage unit forms may be added such as plasticizers, lubricants,excipients, diluents and the like.

Methods of treatment of various pathologies contemplated by the presentinvention involve the administration of therapeutically effectiveamounts of the admixture to mammals in need of such treatment.Administration is by means known to those skilled in the art.Preferably, administration is systemic and most preferably, it is oral.

Pathologies which are effectively treated with the organic acidadmixture described herein include but are not limited to acidosis;viral infections including, but not limited to, cytomaglovirus andhepatitis infections; tumors; and bacterial and fungal infections,including but not limited to S. aureus, E. coli, and C. albicans.

All of these pathologies are well known to those skilled in the art, andtheir diagnosis would be evident to one skilled in the art. For example,acidosis is reflected by abnormally acidic blood pH and/or urine pH.Normal blood pH ranges from about 7.3 to about 7.38, and normal urine pHranges from about 6 to about 8. Viral, bacterial, and fungal infectionscan be confirmed by appropriate assay methods. Other diseases such aschronic fatigue syndrome are only diagnosed through clinicalobservations. Various opportunistic infections which are characteristicof AIDS including, but not limited to, cytomegalovirus, hepatitis, andthe like are effectively treated as described herein.

The amount of the admixture necessary to treat acidosis is ananti-acidosis effective amount. Similarly, the amounts of the admixturenecessary to treat a viral infection, and particularly hepatitis andcytomegalovirus infections are an anti-viral effective amount, andparticularly anti-hepatitis and an anti-cytomegalovirus effectiveamounts. The amount required to treat tumors, and bacterial and fungalinfections are anti-tumor, anti-bacterial, and anti-fungal effectiveamounts, respectively.

The actual amounts of the admixture to be administered will dependindependently upon the age, weight, sex, sensitivity, medical condition,including but not limited to stage of a particular infection or disease,or the like, of an individual. However, the amount will be a safenon-toxic amount.

These amounts can be determined by experimentation well-known in the artsuch as by establishing a matrix of dosages and frequencies andassigning a group of experimental subjects to each point in the matrix.Typically, that amount will range from about 1000 to about 2000milligrams per day for a 150 pound man and preferably about 1500milligrams per day for a 150 pound man. Appropriate dosages fordifferent body weights can be calculated from this.

A daily dosage identifies the average amount of the mixture administeredto an individual. Although the daily dosage may actually be administereddaily, it need not be administered daily. The daily dosage is merely anaverage dosage that an individual receives when the mixture isadministered over a period of time. The daily dosage can be administeredin divided portions so that the total amount administered is the dailydosage.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The following examples illustrate the invention without limitation. Allamounts are given as parts by weight (pbw).

EXAMPLE 1

An admixture of 24 parts by weight of sorbic acid, 40 parts by weight ofaconitic acid, 16 parts by weight of malic acid, 16 parts by weight offumaric acid, and 4 parts by weight of crotonic acid was applied, invarious dilutions, to cut filter paper, and the filter paper wasoverlayed on plates streaked with bacteria. Results are illustrated inTable 1.

                  TABLE 1                                                         ______________________________________                                        Bacterial Assays                                                                Admix-                  Pseudo-                                               ture   monas Escheri-                                                         Dilu- Asper- Staph. aeru- chia Candida                                        tion gillus aureus ginosa coli albicans pH                                  ______________________________________                                        Full   -       1.6 cm   -     1.1 cm 1.6 cm 2.2                                 Strength                                                                      1:10 - - - - - 4.6                                                            1:100 - - - - - 5.2                                                         ______________________________________                                         The (-) negative means that no inhibition was observed.                  

EXAMPLE 2

A patient had a temperature of 101° F. and symptoms of acute urinary andprostate infection. The patient was treated with 1500 mg/day of anadmixture of 24 pbw of sorbic acid, 40 pbw of aconitic acid, 16 pbw ofmalic acid, 16 parts by weight of fumaric acid, and 4 pbw of crotonicacid based upon 100 pbw of total admixture for ten days. Symptoms andtemperature subsided by the 4th or 5th day. Antimicrobial and alkalizingactivity and therapeutic effects of the admixture are illustrated inTable 2. Cultures which were positive for streptococci were negative bythe third week.

                  TABLE 2                                                         ______________________________________                                        Urinary Infection                                                                                Initial Treatment                                                                           Day                                            Laboratory Test Day 1 10 Day 32                                             ______________________________________                                        URINALYSIS                                                                      pH 5.5 8 6                                                                    Protein 1+  0 0                                                             WBC            20-30         2-4    2-4                                       Bacteria       many          0      few                                       Urine Culture  Strept. +     ±   0                                         Blood PSA (normal 0-4)                                                                       21.9          5.1    3.22                                        WBC 10.4  6.1                                                               ______________________________________                                    

EXAMPLE 3

Six HIV positive individuals with average urine pH at breakfast, lunch,and dinner of 6.0, as measured by pHydrion tape, were administered 1500mg/day of an admixture of 24 pbw of sorbic acid, 40 pbw of aconiticacid, 16 pbw of malic acid, 16 pbw of fumaric acid, and 4 pbw ofcrotonic acid.

After one month, average urine pH was raised to 6.3. Previously, it wasfixed at 6.0. Results are illustrated in Table 3 below.

                  TABLE 3                                                         ______________________________________                                        Acidosis                                                                                  Urine pH      Urine pH                                                                             Urine pH                                       Patient Breakfast Lunch Dinner                                              ______________________________________                                        "A"     6.0           6.2      6.2                                               6.0 6.2 6.0                                                                   6.4 6.2 6.2                                                                  "B" 6.2 6.4 6.2                                                                6.0 6.0 6.4                                                                   6.2 6.4 6.2                                                                  "C" 6.0 6.0 6.2                                                                6.0 6.2 6.0                                                                   6.0 6.0 6.2                                                                  "D" 6.0 6.0 6.2                                                                6.0 6.2 6.2                                                                   6.0 6.0 6.2                                                                  "E" 6.0 6.4 6.4                                                                6.2 6.2 6.2                                                                   6.0 6.0 6.2                                                                  "F" 6.0 6.4 6.4                                                                6.2 6.2 6.2                                                                   6.0 6.2 6.2                                                                ______________________________________                                    

EXAMPLE 4

A patient with urine culture positive for cytomegalovirus infection wastreated with 1500 mg/day of an admixture of 24 pbw of sorbic acid, 40pbw of aconitic acid, 16 pbw of malic acid, 16 pbw of fumaric acid, and4 pbw of crotonic acid, based upon 100 pbw of total admixture for sixweeks. After six weeks, a cytomegalovirus urine culture was negative.

EXAMPLE 5

A patient having cancer of the prostate with a PSA of 17 was treatedwith Zolodex™. PSA was lowered to 2.4. Seven months after Zolodextreatment was discontinued, PSA rose to 13.

The patient then received 1500 mg/day of an admixture of 24 pbw ofsorbic acid, 40 pbw of aconitic acid, 16 pbw of malic acid, 16 pbw offumaric acid, and 4 pbw of crotonic acid based upon 100 pbw of totaladmixture, and PSA was lowered to 1.65. Nightly urination decreased from5-6 times/night to two times/night and the patient's general energyincreased 80%.

EXAMPLE 6

A patient was diagnosed with a pancreatic mass. The patient also hadnausea, pain, an inability to eat, weight loss, and weakness.

The patient, who weighed about less than eighty pounds, was given 50mg/day of an admixture of 24 pbw of sorbic acid, 40 pbw of aconiticacid, 16 pbw of malic acid, 16 pbw of fumaric acid, and 4 pbw ofcrotonic acid based upon 100 pbw of total admixture for two months. Thepatient's nausea abated, her appetite improved, she slept morerestfully, and she did not urinate as frequently at night. Theepigastric mass was no longer palpable.

EXAMPLE 7

A patient underwent a resection of a recurrent bladder tumor, at whichtime, the pathological specimen revealed Grade II/III moderatelydifferentiated papillary transitional cell carcinoma with invasion ofthe muscularis of the urinary bladder and of the prostate. The patientwas placed on a protocol of 1500 mg/day of an admixture of 24 pbw ofsorbic acid, 40 pbw of aconitic acid, 16 pbw of malic acid, 16 pbw offumaric acid, and 4 pbw of crotonic acid based upon 100 pbw of totaladmixture. A repeat cystoscopy two months later showed only severalsmall papillary lesions in the urinary bladder and a small lesion in theprostatic urethra. Rectal examination was unremarkable. CAT SCANconfirmed the improvement observed by cystoscopy.

EXAMPLE 8

A patient was diagnosed with long standing Hepatitis C. The patient wastreated with 1500 mg/day of an admixture of 24 pbw of sorbic acid, 40pbw of aconitic acid, 16 pbw of malic acid, 16 pbw of fumaric acid, and4 pbw of crotonic acid based upon 100 pbw of total admixture. After onemonth, pain in the patient's side subsided. The patient was no longernauseated and generally felt better. His SGOT laboratory value went downfrom 68 to 37.

EXAMPLE 9

An admixture of 24 pbw of sorbic acid, 40 pbw of aconitic acid, 16 pbwof malic acid, 16 pbw of fumaric acid, and 4 pbw of crotonic acid basedupon 100 pbw of total admixture was tested for virucidal effectivenessagainst Cytomegalovirus. The viral inoculum was diluted 1:10 with theadmixture. The test material/virus mixture was sampled at 3 and 6minutes. The treated viral mixture was neutralized and titered. Aninitial viral titer was determined.

The challenge organism was Cytomegalovirus, (CMV) and the host cell linewas MRC-5, ATCC CCL-171. Reagents and media were EMEM with Earle's saltssupplemented with heat inactivated fetal bovine serum (FBS), glutamine,and penicillin streptomycin (MEM complete); sterile phosphate bufferedsaline; and newborn calf serum (NBCS).

The virus stock culture was titered and adjusted to containapproximately 10⁷ CCID₅₀ /ml (50% cell-culture infectious doses permilliliter) and stored in liquid nitrogen until use. The virus stock wasthawed and was diluted 10-fold in MEM through 10⁷. One ml aliquots ofappropriate dilutions were plated onto 5 confluent MRC-5 monolayers. Thecells were incubated at 37±1° C., in 5% CO₂, for 2 hours to allow thevirus to adsorb to the cells. After adsorption, the medium was withdrawnfrom the monolayers, the cells were washed once with PBS, and refed withMEM. The monolayers were incubated for 14 days at 37±1° C., in 5% CO₂,and subsequently were observed for virus-specific cytopathogenic effects(CPE).

The test solution was tested by combining the virus with the admixtureat a 1:10 dilution. This suspension was agitated continuously at aconstant temperature of 25° C. and samples were withdrawn at 3 and 6minutes to determine a survivor curve and to calculate a D-value.

The sampled suspensions were neutralized with a 1:1 dilution in new-borncalf serum and were diluted ten-fold in MEM. One ml aliquots of theneutralized mixture were plated onto MRC-5 monolayers (four wells perdilution) and were incubated at 37∓1° C. in a 5% CO₂ in air atmospherefor 2 hours. Following the incubation period, the fluids were removed.The monolayers were washed with PBS, refed MEM and were incubated at37±1° C. in a 5% CO₂ in air atmosphere for thirteen days.

Control virus stock was titered at the time of the test as described, toconfirm that the titer was in an acceptable range. The maintenance ofthe virus titer was evaluated using PBS instead of the test solution.Samples were taken less than 15 seconds after the initiation of the test(zero time control) and after 6 minutes (final time control). Theaverage CCID₅₀ /ml for each titer was determined by the Reed and Muenchmethod. American Journal of Hygiene, 1938, 27:493. The D-value wascalculated by the Stumbo method. Stumbo, C. R., Thermobacteriology infood processing, New York Academic Press (1973), pp. 235-247.

No CPE was observed at 3 minutes. A D-value calculated using this timeresulted in a D-value of 45 seconds. This is an estimate since the firstsampling was done at 3 minutes (no data were collected at less than 3minutes).

When a survivor curve was determined in this test, the admixtureprovided data used to calculate a D-value of 45 seconds (estimated). Aconclusion can be drawn that the admixture was antiviral againstcytomegalovirus.

Results are illustrated in Tables 4, 5, and 6 below.

                  TABLE 4                                                         ______________________________________                                        Test and Control Titers Expressed as CPE                                        Day 13 Results                                                                                             TEST                                             PBS SOLUTION                                                                DILUTION                                                                              VIRUS STOCK  Zero     6 min  3 min                                                                              6 min                               ______________________________________                                        10.sup.-1                                                                             NA           ++++     ++++   ---- ----                                  10.sup.-2 ++++ ++++ ++++ ---- ----                                            10.sup.-3 ++++ ++++ ++++ ---- ----                                            10.sup.-4 ++++ +-+- +-+- ---- ----                                            10.sup.-5 ++++ ---- ---- ---- ----                                            10.sup.-6 ---- ---- ---- ---- ----                                            10.sup.-7 ---- N/A N/A N/A N/A                                                CCID.sub.50 /ml 3.2 × 10.sup.5 1 × 10.sup.4 1 ×                                                     10.sup.4                            ______________________________________                                         + = CPE observed                                                              - = No CPE observed                                                           CT = Cytotoxicity observed                                                    O = No Cytotoxicity observed                                             

                  TABLE 5                                                         ______________________________________                                        Control and Test Titers at Time Intervals                                       After Exposure to Scam Disinfectant                                                SAMPLE      CCID.sub.50 /ml                                            ______________________________________                                        Sample         3.2 × 10.sup.5                                             PBS at Zero time   1 × 10.sup.4                                         PBS at 6 minutes   1 × 10.sup.4                                         3 minutes No CPE observed                                                     6 minutes No CPE observed                                                   ______________________________________                                    

                  TABLE 6                                                         ______________________________________                                        Determination of the D-Value                                                  ______________________________________                                          #STR1##                                                                     ______________________________________                                         Tx = end of time interval                                                     To = beginning of time interval                                               AO = CCID.sub.50 /ml at To                                                    AX = CCID.sub.50 /ml at Tx                                               

EXAMPLE 10

A 36 year old male with well controlled HIV infection had progressivelydeteriorating kidney function from no demonstrable cause. He averaged 5×nocturia and ran a consistently 3 plus albuminuria with urinary specificgravity fixed at 1.005 (normal to 1.030).

After approximately 4 months of 1500 mg/day of admixture of 24 pbw ofsorbic acid, 40 pbw of aconitic acid, 16 pbw of malic acid, 16 pbw offumaric acid, and 4 pbw of crotonic acid based upon 100 pbw of totaladmixture, his kidney function normalized. His three plus albuminuriagradually became negative; he became able to sleep through nights, andthe specific gravity of his urine by concentration test increased to1.0020. His urinary pH, which had been fixed at 5-6 resumed a normalpattern of morning aciduria, increasing to neutral or alkaline duringthe day according to his diet and activity.

Accompanying this was a total regression of his long-existing bilateralmassively swollen parotid glands; the non-specific diagnosis derivedfrom multiple biopsies had been cystic parotitis. The presumptiveretro-diagnosis for parotitis and the kidney insufficiency was severecytomegalovirus (CMV) infection, suggested by high titers of CMVantibodies.

The above mentioned patents, test methods, and publications are herebyincorporated by reference in their entirety.

Many variations of the present invention will suggest themselves tothose skilled in the art in light of the above detailed description. Allsuch obvious variations are within the full intended scope of theappended claims.

What is claimed is:
 1. A method for treating a viral infection in amammal in need of such treatment comprising orally administering to saidmammal, in a systemic, in vivo manner, an anti-viral effective amount ofa composition comprising an admixture comprising:(a) sorbic acid; (b)malic acid; (c) fumaric acid; (d) crotonic acid; and (e) aconitic acid.2. A method for treating cytomegalovirus infection in a mammal in needof such treatment comprising orally administering to said mammal, in asystemic, in vivo manner, an antic-cytomegalovirus effective amount of acomposition comprising an admixture comprising:(a) sorbic acid; (b)malic acid; (c) fumaric acid; (d) crotonic acid; and (e) aconitic acid.3. The method of claim 1, wherein each of components (a), (b), (c), and(d) independently comprise from about 1 to about 50 parts by weight, andcomponent (e) comprises from 1 to about 50, based upon 100 parts of byweight of (a), (b), (c), (d), and (e) combined.
 4. The method of claim2, wherein each of components (a), (b), (c), and (d) independentlycomprise from about 1 to about 50 parts by weight, and component (e)comprises from 1 to about 50, based upon 100 parts of by weight of (a),(b), (c), (d), and (e) combined.
 5. The method of claim 1, whereincomponent (a) comprises from about 5 to about 40 parts by weight,component (b) comprises from about 1 to about 30 party by weight,component (c) comprises from about 1 to about 30 parts by weight, andcomponent (e) comprises from about 1 to about 50 parts by weight, basedupon 100 parts by weight of components (a), (b), (c), (d) and (e)combined.
 6. The method of claim 2, wherein component (a) comprises fromabout 5 to about 40 parts by weight, component (b) comprises from about1 to about 30 party by weight, component (c) comprises from about 1 toabout 30 parts by weight, and component (e) comprises from about 1 toabout 50 parts by weight, based upon 100 parts by weight of components(a), (b), (c), (d) and (e) combined.
 7. The method of claim 1, whereincomponent (a) comprises from about 20 to about 30 parts by weight,component (b) comprises from about 10 to about 20 parts by weight,component (c) comprises from about 10 to about 20 parts by weight,component (d) comprises from about 1 to about 20 parts by weight, andcomponent (e) comprises from about 35 to about 45 parts by weight, basedupon 100 parts by weight of components (a), (b), (c), (d) and (e)combined.
 8. The method of claim 2, wherein component (a) comprises fromabout 20 to about 30 parts by weight, component (b) comprises from about10 to about 20 parts by weight, component (c) comprises from about 10 toabout 20 parts by weight, component (d) comprises from about 1 to about20 parts by weight, and component (e) comprises from about 35 to about45 parts by weight, based upon 100 parts by weight of components (a),(b), (c), (d) and (e) combined.